Depression is a devastating neuropsychiatric disorder and affects approximately 20% of the population. Depression is predicted to be a major cause of morbidity worldwide in the next ten years and will induce an important economic burden (Greenberg, P. E. et al. The economic burden of depression in the United States: how did it change between 1990 and 2000? J Clin Psychiatry 64, 1465 (2003); Moussavi, S. et al. Depression, chronic diseases, and decrements in health: results from the World Health Surveys. Lancet 370, 851, (2007)). Depressions are multifactorial and multigenic diseases characterized by many symptoms like fatigue, anhedonia, pessimism, irritability, sleep troubles, increased or decreased appetite, guiltiness and suicidal tendencies. (Nestler, E. J. et al. Neurobiology of depression. Neuron 34, 13 (2002)). 60 years ago antidepressant treatments had been revolutionized by the discovery of tricyclic antidepressants and monoamine oxidase inhibitors. Later, a second generation of antidepressants was developed with the selective serotonin reuptake or norepinephrine selective reuptake inhibitors. Despite their efficacy, around one third of patients remain unresponsive to these drugs and antidepressants display some adverse side effects and have a long onset of action of at least 2 weeks (Sicouri, S. et al. Sudden cardiac death secondary to antidepressant and antipsychotic drugs. Expert Opin Drug Saf 7, 181, (2008)). Furthermore detecting and preventing depression is costly and is estimated to be about 53 billion dollars per year in the United States alone.
Besides depression in humans, animals including, for example, dogs, cats, horses, monkeys, rats, birds and the like also get depressed. Signs of depression in animals are revealed by their inactivity, changes in appetite, changes in sleep habits, becoming withdrawn or becoming inactive. Eli Lilly researched dog depression and found that 10.4 million dogs in the U.S. alone or 17% suffer from separation anxiety, a type of dog depression. When the drug Reconcile® (Prozac®) was administered to these animals, 73% of the dogs were less depressive as indicated by better behavior.
It was previously demonstrated that the inhibition of the potassium channel TREK-1 led to an antidepressant phenotype (Heurteaux, C. et al. Deletion of the background potassium channel TREK-1 results in a depression-resistant phenotype. Nat Neurosci 9, 1134, (2006)). TREK-1 channels belong to the family of potassium channels with a unique structure characterized by two pore domains and four transmembrane segments in each subunit (Ducroq, J. et al. Dexrazoxane protects the heart from acute doxorubicin-induced QT prolongation: a key role for I(Ks). Br J Pharmacol 159, 93, (2010)). The genes encoding these ion channels are called KCNK (Porsolt, R. D. et al. Depression: a new animal model sensitive to antidepressant treatments. Nature 266, 730, (1977)). It was demonstrated by Kennard et al (Santarelli, L. et al. Requirement of hippocampal neurogenesis for the behavioral effects of antidepressants. Science 301, 805, (2003)) that fluoxetine (Prozac®) and its active metabolite, norfluoxetine inhibit the human two-pore domain potassium channel TREK-1.
This led to the investigation for specific inhibitors of the TREK-1 channel (Mazella, J. et al. Spadin, A sortilin-derived peptide, targeting rodent TREK-1 channels: a new concept in the antidepressant drug design. PLoS Biol 8, e1000355, (2010)). that could be utilized as antidepressants without side effects on both cardiac function and TREK-1 controlled functions (Moha Ou Maati, H. et al. Spadin as a new antidepressant: absence of TREK-1-related side effects. Neuropharmacology 62, 278, (2012)). A peptide named spadin was discovered, which resulted from modification of the sortilin receptor (Mazella, J. et al. The 100-kDa neurotensin receptor is gp95/sortilin, a non-G-protein-coupled receptor. J Biol Chem 273, 26273, (1998)). Spadin is a 17 amino acid peptide which was designed from a 44 amino acid peptide (called PE, the propeptide of Spadin) released by furin in the late Golgi apparatus during the post-translational maturation of the sortilin receptor (Munck Petersen, C. et al. Propeptide cleavage conditions sortilin/neurotensin receptor-3 for ligand binding. Embo J 18, 595, (1999)). Spadin is able to block the TREK-1 potassium channel current and displays antidepressant effects in different behavioral tests (Mazella, J. et al. Spadin, a sortilin-derived peptide, targeting rodent TREK-1 channels: a new concept in the antidepressant drug design. PLoS Biol 8, e1000355, (2010)). Spadin leads to an in vivo increase in efficacy of 5-HT neurotransmission as evidenced by an increased firing activity of DRN-5-HT neurons.
Additionally, like other antidepressant drugs, spadin is also capable of increasing neurogenesis and serotoninergic transmission. Unlike most of the antidepressants used, which need 21 days to be efficient, spadin has a quicker onset of action since it is able to induce these improvements only after a 4 day treatment (Mazella, J. et al. Spadin, a sortilin-derived peptide, targeting rodent TREK-1 channels: a new concept in the antidepressant drug design. PLoS Biol 8, e1000355, (2010)). In the K2P potassium channel family, spadin is specific for TREK-1 channels (Moha Ou Maati, H. et al. Spadin as a new antidepressant: absence of TREK-1-related side effects. Neuropharmacology 62, 278, (2012)). Moreover, activation of TREK-1 channels was demonstrated to be of benefit in different functions such as general anesthesia, neuroprotection by the way of polyunsaturated fatty acids, pain, ischemia and epilepsy (Alloui, A. et al. TREK-1, a K+ channel involved in polymodal pain perception. Embo J 25, 2368, (2006); Heurteaux, C. et al. Alpha-linolenic acid and riluzole treatment confer cerebral protection and improve survival after focal brain ischemia. Neuroscience 137, 241, (2006); Lauritzen, I. et al. Polyunsaturated fatty acids are potent neuroprotectors. Embo J 19, 1784, (2000); Noel, J. et al. The mechano-activated K+ channels TRAAK and TREK-1 control both warm and cold perception. Embo J 28, 1308, (2009)). Nevertheless, blockade of TREK-1 channels by spadin did not interfere with these functions. In other words spadin is devoid of side effects related to TREK-1 functions (Moha Ou Maati, H. et al. Spadin as a new antidepressant: absence of TREK-1-related side effects. Neuropharmacology 62, 278, (2012)). Importantly, spadin induces no cardiac dysfunctions, systolic pressure and pulses were not affected by a three week spadin treatment and spadin was unable to block the two most important repolarizing currents in heart (IKR IKS) (Moha Ou Maati, H. et al. Spadin as a new antidepressant: absence of TREK-1-related side effects. Neuropharmacology 62, 278, (2012)). Taken together these properties are evidence for considering spadin as a new antidepressant drug.
However, since taking antidepressive drugs involve long term treatments formulating spadin had to be taken into account. Daily dose formulations are usually not effective due to the fact that many patients are non-compliant with taking their medications each day. Furthermore, the bioavailability of spadin could be improved to make the peptide more resistant to protease hydrolysis.
Thus, it is an object of the present invention to find new targets for depression based on TREK-1 inhibition and to develop new molecules with antidepressant activity.
It is another object to find compositions for treating depression with improved bioavailability and very minute side effects.
It is yet another object to provide a pharmaceutical composition that is formulated for a long duration.
These and other objects are achieved by the present invention as evidenced by the summary of the invention, description of the preferred embodiments and the claims.